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2022 Fiscal Year Final Research Report

Study in functional mechanism of neurodegenerative mediators

Research Project

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Project/Area Number 17K08327
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionHimeji Dokkyo University

Principal Investigator

Yagami Tatsurou  姫路獨協大学, 薬学部, 教授 (00363812)

Project Period (FY) 2017-04-01 – 2023-03-31
Keywords神経細胞変性 / アルツハイマー病 / 脳卒中 / 脂質代謝 / アラキドン酸カスケード
Outline of Final Research Achievements

15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inactivated phosphatidyl-3-kinase, leading to the neuronal apoptosis. However, 15d-PGJ2 induces neuronal apoptosis independently of its receptors (CRTH2 and PPARγ). Glycolytic enzymes, adaptor proteins and molecular chaperones have been identified as membrane targets for 15d-PGJ2. To target plasmalemmal proteins but not cytosolic ones, antibodies were applied without permeabilization to neurons. Several antibodies against membrane targets for 15d-PGJ2 induced neuronal death. However, these antibodies inactivated caspase 3, which were activated during the 15d-PGJ2-induced apoptosis. Although the accumulation of ubiquitinated proteins was increased by 15d-PGJ2, it was decreased by these antibodies. Suppression of ubiquitin proteasome pathway (UPP) and stimulation of caspase-3 are involved in neurodegeneration. The present study suggested that activation UPP and inhibition of caspase-3 can induced neurodegeneration different from apoptosis.

Free Research Field

神経薬理

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病等において 15d-PGJ2 増加を示唆する結果が報告され、15d-PGJ2 を含むcyclopentenone 代謝物は、神経変性メディエイターとして認知されつつある。我々は、15d-PGJ2によるアポトーシス誘導機構の一つとしてホスファチジルイノシトール3-キナーゼ(PI3K)の抑制を介していることを明らかにした。また、既知受容体はそのアポトーシスには関与していなかったので、15d-PGJ2 膜標的分子の存在を初めて報告し、その解析を行っている。本研究で得られた15d-PGJ2 膜標的分子は、アルツハイマー病等の治療薬を開発する上で新規標的分子となることが期待されている。

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Published: 2024-01-30  

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